Metabolic Compartmentalization as a Driver of Head and Neck Squamous Cell Carcinoma Aggressiveness
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the 7th leading cancer worldwide with 470,000 deaths per year. Cigarette smoking is the main cause of the disease. Standard of care treatment includes surgery, radiotherapy, and chemotherapy, and is associated with high comorbidities and emergence of recurrences. There is a lack of effective targeted therapies in HNSCC, and recently approved immunotherapy fails in 80% of patients. The 5-year survival rate for HNSCC is around 65%, however it has not markedly improved in the recent decades. Therefore, further characterization of the drivers of HNSCC progression is needed to develop novel treatment strategies and improve patient outcomes. This thesis focuses on studying targetable metabolic dependencies in HNSCC. In 2013, our group discovered that two metabolically distinct compartments co-exist in HNSCC and that this is associated with tumor aggressiveness. The tumor stroma, mainly composed of cancer-associated fibroblasts (CAFs), is highly glycolytic and provides nutrients to adjacent proliferating cancer cells with high mitochondrial oxidative metabolism (OXPHOS). Loss of caveolin-1 (CAV1) and upregulation of the monocarboxylate transporter 4 (MCT4) are markers of glycolytic metabolism and metabolite secretion in CAFs. Upregulation of MCT1 and the translocase of the outer mitochondrial membrane 20 (TOMM20) are markers of metabolite uptake and OXPHOS metabolism in cancer cells. The research presented hereby provides evidence that altering metabolic compartmentalization could be an efficient anti-cancer strategy in HNSCC. Using experimental models that reproduce human HNSCC metabolism, we have pharmacologically, chemically, and genetically manipulated metabolic compartmentalization and determined the effects on cancer cell aggressiveness, tumor growth and inflammation. Pharmacological intervention using the anti-OXPHOS drug metformin impaired tumor growth while inducing apoptosis and decreasing MCT1 in cancer cells, an effect that was dependent on the ability to upregulate CAV1 in fibroblasts. Chemical manipulation by cigarette smoke exposure induced glycolysis and MCT4 expression in fibroblasts, and these reprogrammed fibroblasts promoted metabolic compartmentalization, cancer cell aggressiveness, tumor growth and inflammation. Finally, genetic manipulation of fibroblast MCT4 determined that upregulation of MCT4 in fibroblasts is a driver of HNSCC aggressiveness. Altogether, our work has demonstrated that the metabolic cooperation between CAFs and cancer cells has a major influence in HNSCC progression and is a potentially targetable vulnerability in HNSCC.
Subject Area
Biology|Oncology
Recommended Citation
Domingo Vidal, Marina, "Metabolic Compartmentalization as a Driver of Head and Neck Squamous Cell Carcinoma Aggressiveness" (2022). ProQuest ETD Collection - Thomas Jefferson University. AAI29063499.
https://jdc.jefferson.edu/dissertations/AAI29063499
